The PA endonuclease inhibitor RO-7 protects mice from lethal challenge with influenza A or B viruses

Antimicrobial Agents and Chemotherapy

Volumn 61, Issue 5, 2017, Pages

  Jones, Jeremy C ^a   Marathe, Bindumadhav M ^a   Vogel, Peter ^a   Gasser, Rodolfo ^b   Najera, Isabel ^b   Govorkova, Elena A ^a  

^a ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Antiviral; Antiviral agents; Influenza A virus; Influenza B virus; Mouse model; PA endonuclease; PA polymerase

Indexed keywords

ANTIVIRUS AGENT; OSELTAMIVIR; PA ENDONUCLEASE INHIBITOR; RO 7; UNCLASSIFIED DRUG; ENDONUCLEASE; ENZYME INHIBITOR; GUANINE; RING-OPENED 7-(2-HYDROXYETHYL)GUANINE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIGENIC VARIATION; ANTIVIRAL ACTIVITY; ANTIVIRAL THERAPY; ARTICLE; CONTROLLED STUDY; DISEASE SEVERITY; DOSE RESPONSE; DRUG EFFICACY; DRUG SAFETY; FEMALE; GENOTYPE; IN VIVO STUDY; INFECTION PREVENTION; INFLUENZA A; INFLUENZA A VIRUS; INFLUENZA A VIRUS (H1N1); INFLUENZA B; INFLUENZA B VIRUS; LETHALITY; LOW DRUG DOSE; LUNG HOMOGENATE; LUNG INJURY; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; SURVIVAL; VIRUS REPLICATION; VIRUS TITRATION; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; ANTIBIOTIC PROPHYLAXIS; BAGG ALBINO MOUSE; CELL LINE; DOG; DRUG EFFECTS; MDCK CELL LINE; ORTHOMYXOVIRUS INFECTION; POST EXPOSURE PROPHYLAXIS; VIRUS LOAD;

ANIMALS; ANTIBIOTIC PROPHYLAXIS; ANTIVIRAL AGENTS; CELL LINE; DOGS; ENDONUCLEASES; ENZYME INHIBITORS; FEMALE; GUANINE; INFLUENZA A VIRUS; INFLUENZA B VIRUS; MADIN DARBY CANINE KIDNEY CELLS; MICE; MICE, INBRED BALB C; ORTHOMYXOVIRIDAE INFECTIONS; POST-EXPOSURE PROPHYLAXIS; VIRAL LOAD; VIRUS REPLICATION;

EID: 85018185280     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.02460-16     Document Type: Article

References (63)

1. World Health Organization. 2008. Influenza. World Health Organization, Geneva, Switzerland. http://www.who.int/immunization/topics/influenza/en/.
2. Hannoun C. 2013. The evolving history of influenza viruses and influenza vaccines. Expert Rev Vaccines 12:1085-1094. https://doi.org/10.1586/14760584.2013.824709.
3. Soema PC, Kompier R, Amorij JP, Kersten GF. 2015. Current and next generation influenza vaccines: Formulation and production strategies. Eur J Pharm Biopharm 94:251-263. https://doi.org/10.1016/j.ejpb.2015.05.023.
4. Thompson WW, Comanor L, Shay DK. 2006. Epidemiology of seasonal influenza: use of surveillance data and statistical models to estimate the burden of disease. J Infect Dis 194(Suppl 2):S82-S91. https://doi.org/10.1086/507558.
5. Grijalva CG, Zhu Y, Williams DJ, Self WH, Ampofo K, Pavia AT, Stockmann CR, McCullers J, Arnold SR, Wunderink RG, Anderson EJ, Lindstrom S, Fry AM, Foppa IM, Finelli L, Bramley AM, Jain S, Griffin MR, Edwards KM. 2015. Association between hospitalization with community-acquired laboratoryconfirmed influenza pneumonia and prior receipt of influenza vaccination. JAMA 314:1488-1497. https://doi.org/10.1001/jama.2015.12160.
6. Centers for Disease Control and Prevention. 2015. Key facts about seasonal flu vaccine. Centers for Disease Control and Prevention, Atlanta, GA. http://www.cdc.gov/flu/protect/keyfacts.htm#benefits.
7. Peiris JS, Cowling BJ, Wu JT, Feng L, Guan Y, Yu H, Leung GM. 2016. Interventions to reduce zoonotic and pandemic risks from avian influenza in Asia. Lancet Infect Dis 16:252-258. https://doi.org/10.1016/S1473-3099(15)00502-2.
8. Liu Q, Liu DY, Yang ZQ. 2013. Characteristics of human infection with avian influenza viruses and development of new antiviral agents. Acta Pharmacol Sin 34:1257-1269. https://doi.org/10.1038/aps.2013.121.
9. Claes F, Morzaria SP, Donis RO. 2016. Emergence and dissemination of clade 2.3.4.4 H5Nx influenza viruses-how is the Asian HPAI H5 lineage maintained. Curr Opin Virol 16:158-163. https://doi.org/10.1016/j.coviro.2016.02.005.
10. Centers for Disease Control and Prevention. 2015. Antiviral drugs. Centers for Disease Control and Prevention, Atlanta, GA. http://www.cdc.gov/flu/professionals/antivirals/index.htm.
11. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM, Centers for Disease Control and Prevention. 2011. Antiviral agents for the treatment and chemoprophylaxis of influenza-recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 60:1-24.
12. Yen HL. 2016. Current and novel antiviral strategies for influenza infection. Curr Opin Virol 18:126-134. https://doi.org/10.1016/j.coviro.2016.05.004.
13. Boivin G. 2013. Detection and management of antiviral resistance for influenza viruses. Influenza Other Respir Viruses 7(Suppl 3):S18-S23.
14. Webster RG, Govorkova EA. 2014. Continuing challenges in influenza. Ann N Y Acad Sci 1323:115-139. https://doi.org/10.1111/nyas.12462.
15. Centers for Disease Control and Prevention. 2015. Antiviral drug resistance among influenza viruses. Centers for Disease Control and Prevention, Atlanta, GA. http://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm.
16. Okomo-Adhiambo M, Fry AM, Su S, Nguyen HT, Elal AA, Negron E, Hand J, Garten RJ, Barnes J, Xiyan X, Villanueva JM, Gubareva LV, US Influenza Antiviral Group. 2015. Oseltamivir-resistant influenza A(H1N1)pdm09 viruses, United States, 2013-14. Emerg Infect Dis 21:136-141. https://doi.org/10.3201/eid2101.141006.
17. Burnham AJ, Baranovich T, Govorkova EA. 2013. Neuraminidase inhibitors for influenza B virus infection: efficacy and resistance. Antiviral Res 100:520-534. https://doi.org/10.1016/j.antiviral.2013.08.023.
18. Farrukee R, Mosse J, Hurt AC. 2013. Review of the clinical effectiveness of the neuraminidase inhibitors against influenza B viruses. Expert Rev Anti Infect Ther 11:1135-1145. https://doi.org/10.1586/14787210.2013.842466.
19. Kamali A, Holodniy M. 2013. Influenza treatment and prophylaxis with neuraminidase inhibitors: a review. Infect Drug Resist 6:187-198. https://doi.org/10.2147/IDR.S36601.
20. Du Bois RM, Slavish PJ, Baughman BM, Yun MK, Bao J, Webby RJ, Webb TR, White SW. 2012. Structural and biochemical basis for development of influenza virus inhibitors targeting the PA endonuclease. PLoS Pathog 8:e1002830. https://doi.org/10.1371/journal.ppat.1002830.
21. Reich S, Guilligay D, Pflug A, Malet H, Berger I, Crepin T, Hart D, Lunardi T, Nanao M, Ruigrok RW, Cusack S. 2014. Structural insight into capsnatching and RNA synthesis by influenza polymerase. Nature 516: 361-366. https://doi.org/10.1038/nature14009.
22. Stevaert A, Naesens L. 2016. The influenza virus polymerase complex: an update on its structure, functions, and significance for antiviral drug design. Med Res Rev 36:1127-1173. https://doi.org/10.1002/med.21401.
23. Rodriguez-Frandsen A, Alfonso R, Nieto A. 2015. Influenza virus polymerase: functions on host range, inhibition of cellular response to infection and pathogenicity. Virus Res 209:23-38. https://doi.org/10.1016/j.virusres.2015.03.017.
24. Shi F, Xie Y, Shi L, Xu W. 2013. Viral RNA polymerase: a promising antiviral target for influenza A virus. Curr Med Chem 20:3923-3934. https://doi.org/10.2174/09298673113209990208.
25. Guilligay D, Tarendeau F, Resa-Infante P, Coloma R, Crepin T, Sehr P, Lewis J, Ruigrok RW, Ortin J, Hart DJ, Cusack S. 2008. The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol 15:500-506. https://doi.org/10.1038/nsmb.1421.
26. Yuan S, Chu H, Zhang K, Ye J, Singh K, Kao RY, Chow BK, Zhou J, Zheng BJ. 2016. A novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication. J Antimicrob Chemother 71:2489-2497. https://doi.org/10.1093/jac/dkw194.
27. Hsu JT, Yeh JY, Lin TJ, Li ML, Wu MS, Hsieh CF, Chou YC, Tang WF, Lau KS, Hung HC, Fang MY, Ko S, Hsieh HP, Horng JT. 2012. Identification of BPR3P0128 as an inhibitor of cap-snatching activities of influenza virus. Antimicrob Agents Chemother 56:647-657. https://doi.org/10.1128/AAC.00125-11.
28. Roch FF, Hinterkorner G, Menke J, Tang GQ, Cusack S, Butzendobler B, Buschmann H, Datta K, Wolkerstorfer A. 2015. An RNA hybridization assay for screening influenza A virus polymerase inhibitors using the entire ribonucleoprotein complex. Assay Drug Dev Technol 13:488-506. https://doi.org/10.1089/adt.2015.668.
29. Lv HM, Guo XL, Gu RX, Wei DQ. 2011. Free energy calculations and binding analysis of two potential anti-influenza drugs with Polymerase basic protein-2 (PB2). Protein Pept Lett 18:1002-1009. https://doi.org/10.2174/092986611796378675.
30. Li C, Ba Q, Wu A, Zhang H, Deng T, Jiang T. 2013. A peptide derived from the C terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly. FEBS J 280:1139-1149. https://doi.org/10.1111/febs.12107.
31. Chase G, Wunderlich K, Reuther P, Schwemmle M. 2011. Identification of influenza virus inhibitors which disrupt of viral polymerase proteinprotein interactions. Methods 55:188-191. https://doi.org/10.1016/j.ymeth.2011.08.007.
32. Boyd MJ, Bandarage UK, Bennett H, Byrn RR, Davies I, Gu W, Jacobs M, Ledeboer MW, Ledford B, Leeman JR, Perola E, Wang T, Bennani Y, Clark MP, Charifson PS. 2015. Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors. Bioorg Med Chem Lett 25:1990-1994. https://doi.org/10.1016/j.bmcl.2015.03.013.
33. Byrn RA, Jones SM, Bennett HB, Bral C, Clark MP, Jacobs MD, Kwong AD, Ledeboer MW, Leeman JR, McNeil CF, Murcko MA, Nezami A, Perola E, Rijnbrand R, Saxena K, Tsai AW, Zhou Y, Charifson PS. 2015. Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob Agents Chemother 59:1569-1582. https://doi.org/10.1128/AAC.04623-14.
34. Blair W, Cox C. 2016. Current landscape of antiviral drug discovery. F1000Res 5:F1000 Faculty Rev-202. https://doi.org/10.12688/f1000 research.7665.
35. Dias A, Bouvier D, Crepin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW. 2009. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 458:914-918. https://doi.org/10.1038/nature07745.
36. El Hefnawi M, Alaidi O, Mohamed N, Kamar M, El-Azab I, Zada S, Siam R. 2011. Identification of novel conserved functional motifs across most influenza A viral strains. Virol J 8:44. https://doi.org/10.1186/1743-422X-8-44.
37. Stevaert A, Nurra S, Pala N, Carcelli M, Rogolino D, Shepard C, Domaoal RA, Kim B, Alfonso-Prieto M, Marras SA, Sechi M, Naesens L. 2015. An integrated biological approach to guide the development of metalchelating inhibitors of influenza virus PA endonuclease. Mol Pharmacol 87:323-337. https://doi.org/10.1124/mol.114.095588.
38. Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, Lv Z, Ge R, Li X, Deng T, Fodor E, Rao Z, Liu Y. 2009. Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature 458: 909-913. https://doi.org/10.1038/nature07720.
39. Jones JC, Marathe BM, Lerner C, Kreis L, Gasser R, Pascua PN, Najera I, Govorkova EA. 2016. A novel endonuclease inhibitor exhibits broadspectrum anti-influenza activity in vitro. Antimicrob Agents Chemother 60:5504-5514. https://doi.org/10.1128/AAC.00888-16.
40. Hastings JC, Selnick H, Wolanski B, Tomassini JE. 1996. Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors. Antimicrob Agents Chemother 40:1304-1307.
41. Yuan S, Chu H, Singh K, Zhao H, Zhang K, Kao RY, Chow BK, Zhou J, Zheng BJ. 2016. A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase. Sci Rep 6:22880. https://doi.org/10.1038/srep22880.
42. Ilyushina NA, Hay A, Yilmaz N, Boon AC, Webster RG, Govorkova EA. 2008. Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice. Antimicrob Agents Chemother 52:3889-3897. https://doi.org/10.1128/AAC.01579-07.
43. Govorkova EA, Leneva IA, Goloubeva OG, Bush K, Webster RG. 2001. Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother 45:2723-2732. https://doi.org/10.1128/AAC.45.10.2723-2732.2001.
44. T method. Nat Protoc 3:1101-1108. https://doi.org/10.1038/nprot.2008.73.
45. Inagaki K, Song MS, Crumpton JC, De Beauchamp J, Jeevan T, Tuomanen EI, Webby RJ, Hakim H. 2016. Correlation between the interval of influenza virus infectivity and results of diagnostic assays in a ferret model. J Infect Dis 213:407-410. https://doi.org/10.1093/infdis/jiv331.
46. Nakazawa M, Kadowaki SE, Watanabe I, Kadowaki Y, Takei M, Fukuda H. 2008. PA subunit of RNA polymerase as a promising target for antiinfluenza virus agents. Antiviral Res 78:194-201. https://doi.org/10.1016/j.antiviral.2007.12.010.
47. Reber A, Katz J. 2013. Immunological assessment of influenza vaccines and immune correlates of protection. Expert Rev Vaccines 12:519-536. https://doi.org/10.1586/erv.13.35.
48. Barnard DL. 2009. Animal models for the study of influenza pathogenesis and therapy. Antiviral Res 82:A110-A122. https://doi.org/10.1016/j.antiviral.2008.12.014.
49. Sidwell RWS, Smee DF. 2004. Experimental disease models of influenza virus infections: recent developments. Drug Discov Today Dis Models 1:57-63. https://doi.org/10.1016/j.ddmod.2004.01.003.
50. World Health Organization. 2016. Recommended composition of influenza virus vaccines for use in the 2016-2017 northern hemisphere influenza season. World Health Organization, Geneva, Switzerland. http://www.who.int/influenza/vaccines/virus/recommendations/2016-17-north/en/.
51. Fodor E, Crow M, Mingay LJ, Deng T, Sharps J, Fechter P, Brownlee GG. 2002. A single amino acid mutation in the PA subunit of the influenza virus RNA polymerase inhibits endonucleolytic cleavage of capped RNAs. J Virol 76: 8989-9001. https://doi.org/10.1128/JVI.76.18.8989-9001.2002.
52. Yamashita M, Krystal M, Palese P. 1989. Comparison of the three large polymerase proteins of influenza A, B, and C viruses. Virology 171: 458-466. https://doi.org/10.1016/0042-6822(89)90615-6.
53. Song MS, Kumar G, Shadrick WR, Zhou W, Jeevan T, Li Z, Slavish PJ, Fabrizio TP, Yoon SW, Webb TR, Webby RJ, White SW. 2016. Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor. Proc Natl Acad Sci U S A 113:3669-3674. https://doi.org/10.1073/pnas.1519772113.
54. Stevaert A, Dallocchio R, Dessi A, Pala N, Rogolino D, Sechi M, Naesens L. 2013. Mutational analysis of the binding pockets of the diketo acid inhibitor L-742,001 in the influenza virus PA endonuclease. J Virol 87: 10524-10538. https://doi.org/10.1128/JVI.00832-13.
55. ClinicalTrials.gov. 2015. Phase 3 efficacy and safety study of favipiravir for treatment of uncomplicated influenza in adults: T705US316. National Institutes of Health, Bethesda, MD. https://clinicaltrials.gov/ct2/show/NCT02026349?term-favipiravir-influenza&rank-2.
56. Naesens L, Stevaert A, Vanderlinden E. 2016. Antiviral therapies on the horizon for influenza. Curr Opin Pharmacol 30:106-115. https://doi.org/10.1016/j.coph.2016.08.003.
57. Loregian A, Mercorelli B, Nannetti G, Compagnin C, Palu G. 2014. Antiviral strategies against influenza virus: towards new therapeutic approaches. Cell Mol Life Sci 71:3659-3683. https://doi.org/10.1007/s00018-014-1615-2.
58. Cheng CK, Tsai CH, Shie JJ, Fang JM. 2014. From neuraminidase inhibitors to conjugates: a step towards better anti-influenza drugs? Future Med Chem 6:757-774. https://doi.org/10.4155/fmc.14.30.
59. Ilyushina NA, Khalenkov AM, Seiler JP, Forrest HL, Bovin NV, Marjuki H, Barman S, Webster RG, Webby RJ. 2010. Adaptation of pandemic H1N1 influenza viruses in mice. J Virol 84:8607-8616. https://doi.org/10.1128/JVI.00159-10.
60. Reed LM, Muench H. 1938. A simple method for estimating fifty percent endpoints. Am J Hyg 27:493-497.
61. Kawakami E, Watanabe T, Fujii K, Goto H, Watanabe S, Noda T, Kawaoka Y. 2011. Strand-specific real-time RT-PCR for distinguishing influenza vRNA, cRNA, and mRNA. J Virol Methods 173:1-6. https://doi.org/10.1016/j.jviromet.2010.12.014.
62. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. 2013. MEGA6: molecular evolutionary genetics analysis, version 6.0. Mol Biol Evol 30:2725-2729. https://doi.org/10.1093/molbev/mst197.
63. Kim JK, Kayali G, Walker D, Forrest HL, Ellebedy AH, Griffin YS, Rubrum A, Bahgat MM, Kutkat MA, Ali MA, Aldridge JR, Negovetich NJ, Krauss S, Webby RJ, Webster RG. 2010. Puzzling inefficiency of H5N1 influenza vaccines in Egyptian poultry. Proc Natl Acad Sci U S A 107:11044-11049. https://doi.org/10.1073/pnas.1006419107.